Daniel P. Flaherty
Ph.D. - 2010 - University of Nebraska Medical Center (Mentor: Jonathan Vennerstrom)
Postdoc - 2010 - 2014 - University of Kansas, Specialized Chemistry Center (Mentor: Jeffrey Aube)
The Flaherty Lab pursues projects to validate novel therapeutic targets for the treatment of infectious disease, Parkinson's disease and cancer. At our core, we are a medicinal chemistry laboratory; however, in addition to organic synthesis and med chem optimization our lab also pursues assay development, high-throughput screening, biochemical/biophysical ligand-receptor analysis, structural characterization, and computational modeling. Trainees in the Flaherty lab acquire hands on experience in many of these areas to provide a holistic drug discovery training experience. We apply these approaches to the following projects that are currently in progress in the lab:
Inhibitors of Gram-negative Ribonuclease E
Ribonuclease E (RNAse E) is the central nexus of RNA processing and metabolism across all Gram-negative bacterial species. The major component of the RNA degradosome, RNAse E is responsible for processing processing pre-tRNA, maturation of rRNA, and degradation of mRNA. If one process is inhibited then the bacteria is no longer viable. The essential nature of this enzyme makes it an attractive target for validation as a therapeutic strategy. Using a combined fragment- and computational-based approach our lab is currently working to identify and develop first-in-class small molecule inhibitors for RNase E that may be utilized to realize the promise of this target for treating Gram-negative bacterial infections.
Inhibitors of S. aureus RnpA
Ribonuclease P (RNAse P) is a ribozyme that has long been known to process pre-tRNA in bacteria species via cleavage of the 5' leader sequence. However, recent studies have shown that the protein subunit, RnpA, also has a role in mRNA degradation. Previous efforts to develop inhibitors for RnpA have focused on it's role in as a substrate binding domain in the ribozyme. We are tackling this problem from a different point of view and searching for molecules that are dual functional. Using both traditional and fragment-based screening approaches our lab is developing molecules that can inhibit one or both of these RNA metabolism processes as a means to validate targeting the RnpA subunit for small molecule drug discovery.
Modulators of UCHL1 activity
Deubiquitinating enzymes have become increasingly popular drug targets for a variety of indications. This class of enzyme is heavily involved in signaling pathways to turn on/off processes, control cellular trafficking, and sending proteins to degradation through the ubiquitin-proteasome system. Our lab is currently pursuing best-in-class inhibitors versus Ubiquitin C-terminal hydrolase L1 (UCHL1). UCHL1 expression correlates well with tumor size and invasiveness and further studies have shown that it appears to regulate pathways leading to metastasis. Our team is using a traditional and fragment-based approach to discover improved small molecule inhibitors with therapeutic potential to treating aggressive forms of cancer.
Inhibitors of Adenylyl Cyclases
This project is a interdisciplinary collaboration involving four labs within MCMP. Dr. Watts lab has extensive expertise studying the pharmacology of adenylyl cyclases (AC) and has shown that AC1 is a potential target to treat inflammatory pain. This team has embarked upon as small molecule AC1 inhibitor campaign in which the Flaherty lab provides medicinal chemistry support and coordinates with the lab of Dr. Markus Lill for analog design based on computational models. Analogs to the Watts lab for testing and any prioritized molecules move to in vivo studies in Dr. Van Rijn's lab. This project embodies the benefits of housing both medicinal chemistry and pharmacology expertise in the same department. *Data image borrowed from Brust et al, Sci Signal, 2017, 10, eaah5381
Amr Mohamed Elkabbany (Graduate Student)
Lisha Ha (Graduate Student)
Chad Hewitt (Graduate Student)
Ryan D. Imhoff (Graduate Student)
Aaron D. Krabill (Graduate Student)
Anil Kumar Marapaka (Post-Doctoral Research Associate)
Jason Andrew Scott (Graduate Student)
Service and Engagement
Member of the American Chemical Society, Organic and Medicinal Chemistry Divisions.
MCMP 204 - Organic Chemistry I
1. Lopez-Sambrooks, C; Shrimal, S.; Khodier, C.; Flaherty, D.P.; Charest, J.; Gao, N.; Lewis, T. A.; Lehrman, M. A.; Gilmore, R. Golden, J.; Contessa, J. N. Oligosaccharyltransferase inhibition induces senescence in RTK-driven tumor cells. Nat. Chem. Biol. 2016, 12, 1023 - 1030.
2. Perlmutter, J. I.; Forbes, L. T.; Krysan, D. J.; Ebsworth-Mojica, E.; Dunman, P. M.; Flaherty, D. P.*; Repurposing the antihistamine terfenadine for antimicrobial activity against Staphylococcus aureus. J. Med. Chem. 2014, 57, 8540 - 8562
2. Flaherty, D. P.; Miller, J. R.; Garshott, D. M.; Hedrock, M.; Gosalia, P.; Li, Y.; Milewski, M.; Sugarman, E.; Suyama, E.; Nguyen, K.; Vasile, S.; Salaniwal, S.; Stonich, D.; Su, Y.; Vicchiarelli, M.; Chung, T. D. Y.; Pinkerton, A. B.; Aubé, J.; Callaghan, M. U.; Golden, J. E.' Fribley, A. M.; Kaufman, R. J. Discovery and development of selective activators targeting the apoptotic CHOP pathway of the unfolded protein response. ACS Med. Chem. Lett. 2014, 5, 1278 - 1283.
3. Matharu, D. S.; Flaherty, D. P.; Simpson, D. S; Chung, D.; Yan, D.; Noah, J. W.; Jonsson, C. B.; White, E. L.; Aubé, J.; Plemper, R. K.; Severson, W. E.; Golden, J. E. Optimization of potent and selective quinazolinediones: inhibitors of respiratory syncytial virus that block RNA-dependent-RNA-polymerase complex activity. J. Med. Chem. 2014, 57, 10314 – 10328.
4. Flaherty, D. P.; Simpson, D. S.; Miller, M.; Maki, B. E.; Zou, B.; Shi, J.; Wu, M.; McManus, O. B.; Aubé, J.; Li, M.; Golden, J. E. Potent and selective inhibitors of the TASK-1 potassium channel through chemical optimization of a bis-amide scaffold. Bioorg. Med. Chem. Lett. 2014, 24, 8540 - 8562.
5. Harris, M. T.; Walker, D. M.; Drew, M. E.; Mitchell, W. G.; Dao, K.; Schroeder, C. E.; Flaherty, D. P.; Weiner, W. S.; Golden, J. E.; Morris, J. C. Interrogating a hexokinase-selected small molecule library for inhibitors of Plasmodium falciparum hexokinase. Antimicrob. Agents Chemother. 2013, 57, 3731 - 3737.